The members of the University of Colorado Autoimmunity Center of Excellence (Colorado ACE) are proposing two Clinical Projects and one Collaborative Project. The overall Center has been constructed with a focus on two areas. The first is the development of innovative therapeutic strategies, in the Primary Clinical Project with regard to the mechanism of effect of the therapeutic on HLA-peptide interaction in Type 1 Diabetes (T1D) and in the Alternate Clinical Project with regard to the focus on prevention of the onset of clinically apparent disease in Rheumatoid Arthritis (RA). Studies in the Collaborative Project are intended to substantially increase our understanding of the specific immune mechanisms underlying exacerbation and remission of a human disease, neuromyelitis optica, in which the pathogenic process is driven by B and T cell recognition of a well-defined autoantigen, aquaporin 4. In addition, because of recent increases in our understanding of antigen-specific responses in T1D and RA, we will also be able to determine in the Clinical Projects how therapeutic intervention not only affects clinical outcomes but also relevant antigen-specific responses. To address the stated goals, the investigators of the Colorado ACE propose three Specific Aims: Specific Aim #1: Evaluate the ability of novel therapeutic strategies designed to interrupt/modulate MHC Class II molecular interactions with peptides to lead to amelioration of organ-specific and non-specific autoimmunity. Specific Aim #2: Develop, test and evaluate the immunomodulatory effects and clinical benefit of treatment strategies that are focused on prevention of the clinical onset of rheumatoid arthritis and other autoimmune diseases in extraordinarily high-risk subjects. Specific Aim #3: Develop an understanding of the alterations to B and T cell autoantigen-specific responses that are associated with clinical responses to targeted therapeutics and change in clinical status. Finally, with a large and varied clinical population, a strong history of successful clinical studies and trials performed in a highly collaborative manner, and broad experience in clinical phenotyping and biomarker development, the Colorado ACE investigators will provide an important resource to the newly constituted ACE Consortium.